Novel 3-Aza-Spiro[5.5]Undecane Derivatives and Their Use As Monoamine Neurotransmitter Re-Uptake Inhibitors

ABSTRACT

This invention relates to novel 3-aza-spiro[5.5]undecane derivatives useful as monoamine neurotransmitter re-uptake inhibitors. 
     In other aspects the invention relates to the use of these compounds in a method for therapy and to pharmaceutical compositions comprising the compounds of the invention.

TECHNICAL FIELD

This invention relates to novel 3-aza-spiro[5.5]undecane derivativesuseful as monoamine neurotransmitter re-uptake inhibitors.

In other aspects the invention relates to the use of these compounds ina method for therapy and to pharmaceutical compositions comprising thecompounds of the invention.

BACKGROUND ART

Serotonin Selective Reuptake Inhibitors (SSRIs) currently provideefficacy in the treatment of several CNS disorders, including depressionand panic disorder. SSRIs are generally perceived by psychiatrists andprimary care physicians as effective, well-tolerated and easilyadministered. However, they are associated with a number of undesirablefeatures.

Thus, there is still a strong need for compounds with an optimisedpharmacological profile as regards the activity on reuptake of themonoamine neurotransmitters serotonin, dopamine and noradrenaline, suchas the ratio of the serotonin reuptake versus the noradrenaline anddopamine reuptake activity.

SUMMARY OF THE INVENTION

In its first aspect, the invention provides a compound of Formula I:

any of its isomers or any mixture of its isomers, or a pharmaceuticallyacceptable salt thereof,wherein R^(a), R^(b) and X are as defined below.

In its second aspect, the invention provides a pharmaceuticalcomposition, comprising a therapeutically effective amount of a compoundof the invention, any of its isomers or any mixture of its isomers, or apharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier, excipient or diluent.

In a further aspect, the invention provides the use of a compound of theinvention, any of its isomers or any mixture of its isomers, or apharmaceutically acceptable salt thereof, for the manufacture of apharmaceutical composition for the treatment, prevention or alleviationof a disease or a disorder or a condition of a mammal, including ahuman, which disease, disorder or condition is responsive to inhibitionof monoamine neurotransmitter re-uptake in the central nervous system.

In a still further aspect, the invention relates to a method fortreatment, prevention or alleviation of a disease or a disorder or acondition of a living animal body, including a human, which disorder,disease or condition is responsive to inhibition of monoamineneurotransmitter re-uptake in the central nervous system, which methodcomprises the step of administering to such a living animal body in needthereof a therapeutically effective amount of a compound of theinvention, any of its isomers or any mixture of its isomers, or apharmaceutically acceptable salt thereof.

Other objects of the invention will be apparent to the person skilled inthe art from the following detailed description and examples.

DETAILED DISCLOSURE OF THE INVENTION 3-aza-spiro[5.5]undecaneDerivatives

In its first aspect the present invention provides compounds of formulaI:

any of its isomers or any mixture of its isomers,or a pharmaceutically acceptable salt thereof;wherein

R^(a) represents hydrogen or alkyl;

-   -   which alkyl is optionally substituted with one or more        substituents independently selected from the group consisting        of:        -   halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxy,            amino, nitro, alkoxy, cycloalkoxy, alkyl, cycloalkyl,            cycloalkylalkyl, alkenyl and alkynyl; and

R^(b) represents an aryl or a heteroaryl group,

-   -   which aryl or heteroaryl group is optionally substituted with        one or more substituents independently selected from the group        consisting of:        -   halo, trifluoromethyl, trifluoromethoxy, cyano, nitro,            hydroxy, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl,            methylenedioxy, ethylenedioxy, alkyl, cycloalkyl,            cycloalkylalkyl, alkenyl, alkynyl, —NR′R″, —(C═O)NR′R″ or            —NR′(C═O)R″;            -   wherein R′ and R″ independent of each other are hydrogen                or alkyl X represents —O— or —NR^(c)—;    -   wherein R^(c) represents hydrogen or alkyl.

In one embodiment, R^(a) represents hydrogen or alkyl. In a specialembodiment, R^(a) represents hydrogen. In a further embodiment, R^(a)represents alkyl, such as methyl.

In a still further embodiment, R^(b) represents a phenyl group, whichphenyl group is optionally substituted with one or more substituentsindependently selected from the group consisting of: halo,trifluoromethyl, trifluoromethoxy, cyano and alkoxy.

In a further embodiment, R^(b) represents a phenyl group, which phenylgroup is substituted once or twice with substituents independentlyselected from the group consisting of: halo, trifluoromethyl,trifluoromethoxy, cyano and alkoxy.

In a special embodiment, R^(b) represents halophenyl, such aschlorophenyl, such as 4-chlorophenyl. In a further embodiment, R^(b)represents dihalophenyl, such as 3,4-dihalophenyl. In a still furtherembodiment, R^(b) represents dichlorophenyl, such as 3,4-dichlorophenyl.In a further embodiment, R^(b) represents bromo-chlorophenyl, such as3-bromo-4-chloro-phenyl. In a still further embodiment, R^(b) representschloro-fluoro-phenyl, such as 3-chloro-4-fluoro-phenyl or4-chloro-3-fluoro-phenyl. In a further embodiment, R^(b) representshalo-trifluoromethyl-phenyl, such as chloro-trifluoromethyl-phenyl, suchas 4-chloro-3-trifluoromethyl-phenyl.

In a still further embodiment, R^(b) represents a naphthyl group, whichnaphthyl group is optionally substituted with one or more substituentsindependently selected from the group consisting of: halo,trifluoromethyl, trifluoromethoxy, cyano and alkoxy.

In a special embodiment, R^(b) represents naphthyl. In a furtherembodiment, R^(b) represents alkoxynaphthyl, such as methoxynaphthyl,such as 6-methoxy-naphthalen-2-yl.

In a still further embodiment, R^(b) represents an optionallysubstituted coumarinyl group. In a special embodiment, R^(b) representscoumarinyl, such as coumarin-6-yl or coumarin-7-yl.

In a further embodiment, X represents —O—. In a still furtherembodiment, X represents —NR^(c)—. In a further embodiment R^(c)represents hydrogen. In a special embodiment, X represents —O— or —NH—.

In a special embodiment the compound of the invention is

-   9-(3,4-Dichloro-phenoxy)-3-aza-spiro[5.5]undecane;-   9-(6-Methoxy-naphthalen-2-yloxy)-3-aza-spiro[5.5]undecane;-   7-(3-Aza-spiro[5.5]undec-9-yloxy)-chromen-2-one;-   9-(3-Bromo-4-chloro-phenoxy)-3-aza-spiro[5.5]undecane;-   9-(4-Chloro-phenoxy)-3-aza-spiro[5.5]undecane;-   9-(4-Chloro-3-fluoro-phenoxy)-3-aza-spiro[5.5]undecane;-   9-(3-Chloro-4-fluoro-phenoxy)-3-aza-spiro[5.5]undecane;-   9-(4-Chloro-3-trifluoromethyl-phenoxy)-3-aza-spiro[5.5]undecane;-   9-(Naphthalen-2-yloxy)-3-aza-spiro[5.5]undecane;-   6-(3-Aza-spiro[5.5]undec-9-yloxy)-chromen-2-one;-   (3-Aza-spiro[5.5]undec-9-yl)-(3,4-dichloro-phenyl)-amine;-   9-(3,4-Dichloro-phenoxy)-3-methyl-3-aza-spiro[5.5]undecane;    or a pharmaceutically acceptable salt thereof.

Any combination of two or more of the embodiments as described above isconsidered within the scope of the present invention.

DEFINITION OF SUBSTITUENTS

In the context of this invention halo represents fluoro, chloro, bromoor iodo.

In the context of this invention an alkyl group designates a univalentsaturated, straight or branched hydrocarbon chain. The hydrocarbon chainpreferably contains of from one to six carbon atoms (C₁₋₆-alkyl),including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl andisohexyl. In a preferred embodiment alkyl represents a C₁₋₄-alkyl group,including butyl, isobutyl, secondary butyl, and tertiary butyl. Inanother preferred embodiment of this invention alkyl represents aC₁₋₃-alkyl group, which may in particular be methyl, ethyl, propyl orisopropyl.

In the context of this invention an alkenyl group designates a carbonchain containing one or more double bonds, including di-enes, tri-enesand poly-enes. In a preferred embodiment the alkenyl group of theinvention comprises of from two to six carbon atoms (C₂₋₆-alkenyl),including at least one double bond. In a most preferred embodiment thealkenyl group of the invention is ethenyl; 1- or 2-propenyl; 1-, 2- or3-butenyl, or 1,3-butadienyl; 1-, 2-, 3-, 4- or 5-hexenyl, or1,3-hexadienyl, or 1,3,5-hexatrienyl.

In the context of this invention an alkynyl group designates a carbonchain containing one or more triple bonds, including di-ynes, tri-ynesand poly-ynes. In a preferred embodiment the alkynyl group of theinvention comprises of from two to six carbon atoms (C₂₋₆-alkynyl),including at least one triple bond. In its most preferred embodiment thealkynyl group of the invention is ethynyl; 1-, or 2-propynyl; 1-, 2-, or3-butynyl, or 1,3-butadienyl; 1-, 2-, 3-, 4-pentynyl, or1,3-pentadiynyl; 1-, 2-, 3-, 4-, or 5-hexynyl, or 1,3-hexadienyl or1,3,5-hexatrienyl.

In the context of this invention a cycloalkyl group designates a cyclicalkyl group, preferably containing of from three to seven carbon atoms(C₃₋₇-cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

Alkoxy is O-alkyl, wherein alkyl is as defined above.

Cycloalkoxy means O-cycloalkyl, wherein cycloalkyl is as defined above.

Cycloalkylalkyl means cycloalkyl as above and alkyl as above, meaningfor example, cyclopropylmethyl.

In the context of this invention an aryl group designates a carbocyclicaromatic ring system such as phenyl, naphthyl or fluorenyl.

In the context of this invention a heteroaryl group designates anaromatic mono- or bicyclic heterocyclic group, which holds one or moreheteroatoms in its ring structure. Preferred heteroatoms includenitrogen (N), oxygen (O), and sulphur (S).

Preferred monocyclic heteroaryl groups of the invention include aromatic5- and 6-membered heterocyclic monocyclic groups, including for example,but not limited to, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,tetrazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, triazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, imidazolyl, pyrrolyl, pyrazolyl,furanyl, thienyl, pyridyl, pyrimidyl, or pyridazinyl.

Preferred bicyclic heteroaryl groups of the invention include forexample, but not limited to, indolizinyl, indolyl, isoindolyl,indazolyl, benzofuranyl, benzo[b]thienyl, benzimidazolyl, benzoxazolyl,benzooxadiazole, benzothiazolyl, benzo[d]isothiazolyl, purinyl,quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, and indenyl. Included inthe bicyclic heteroaryl group is also coumarinyl.

Pharmaceutically Acceptable Salts

The chemical compound of the invention may be provided in any formsuitable for the intended administration. Suitable forms includepharmaceutically (i.e. physiologically) acceptable salts, and pre- orprodrug forms of the chemical compound of the invention.

Examples of pharmaceutically acceptable addition salts include, withoutlimitation, the non-toxic inorganic and organic acid addition salts suchas the hydro-chloride, the hydrobromide, the nitrate, the perchlorate,the phosphate, the sulphate, the formate, the acetate, the aconate, theascorbate, the benzenesulphonate, the benzoate, the cinnamate, thecitrate, the embonate, the enantate, the fumarate, the glutamate, theglycolate, the lactate, the maleate, the malonate, the mandelate, themethanesulphonate, the naphthalene-2-sulphonate, the phthalate, thesalicylate, the sorbate, the stearate, the succinate, the tartrate, thetoluene-p-sulphonate, and the like. Such salts may be formed byprocedures well known and described in the art.

Other acids such as oxalic acid, which may not be consideredpharmaceutically acceptable, may be useful in the preparation of saltsuseful as intermediates in obtaining a chemical compound of theinvention and its pharmaceutically acceptable acid addition salt.

Examples of pharmaceutically acceptable cationic salts of a chemicalcompound of the invention include, without limitation, the sodium, thepotassium, the calcium, the magnesium, the zinc, the aluminium, thelithium, the choline, the lysinium, and the ammonium salt, and the like,of a chemical compound of the invention containing an anionic group.Such cationic salts may be formed by procedures well known and describedin the art.

In the context of this invention the “onium salts” of N-containingcompounds are also contemplated as pharmaceutically acceptable salts.Preferred “onium salts” include the alkyl-onium salts, thecycloalkyl-onium salts, and the cycloalkylalkyl-onium salts.

Examples of pre- or prodrug forms of the chemical compound of theinvention include examples of suitable prodrugs of the substancesaccording to the invention include compounds modified at one or morereactive or derivatizable groups of the parent compound. Of particularinterest are compounds modified at a carboxyl group, a hydroxyl group,or an amino group. Examples of suitable derivatives are esters oramides.

The chemical compound of the invention may be provided in dissoluble orindissoluble forms together with a pharmaceutically acceptable solventsuch as water, ethanol, and the like. Dissoluble forms may also includehydrated forms such as the monohydrate, the dihydrate, the hemihydrate,the trihydrate, the tetrahydrate, and the like. In general, thedissoluble forms are considered equivalent to indissoluble forms for thepurposes of this invention.

Steric Isomers

It will be appreciated by those skilled in the art that the compounds ofthe present invention exist in different stereoisomeric forms—includingenantiomers, diastereomers and cis-trans-isomers.

The invention includes all such isomers and any mixtures thereofincluding racemic mixtures.

Racemic forms can be resolved into the optical antipodes by knownmethods and techniques. One way of separating the enantiomeric compounds(including enantiomeric intermediates) is—in the case the compound beinga chiral acid—by use of an optically active amine, and liberating thediastereomeric, resolved salt by treatment with an acid. Another methodfor resolving racemates into the optical antipodes is based uponchromatography on an optical active matrix. Racemic compounds of thepresent invention can thus be resolved into their optical antipodes,e.g., by fractional crystallisation of D- or L-(tartrates, mandelates,or camphorsulphonate) salts for example.

The chemical compounds of the present invention may also be resolved bythe formation of diastereomeric amides by reaction of the chemicalcompounds of the present invention with an optically active activatedcarboxylic acid such as that derived from (+) or (−) phenylalanine, (+)or (−) phenylglycine, (+) or (−) camphanic acid or by the formation ofdiastereomeric carbamates by reaction of the chemical compound of thepresent invention with an optically active chloroformate or the like.

Additional methods for the resolving the optical isomers are known inthe art. Such methods include those described by Jaques J, Collet A, &Wilen S in “Enantiomers, Racemates, and Resolutions”, John Wiley andSons, New York (1981).

Optical active compounds can also be prepared from optical activestarting materials or intermediates.

Labelled Compounds

The compounds of the invention may be used in their labelled orunlabelled form. In the context of this invention the labelled compoundhas one or more atoms replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. The labelling will allow easy quantitative detection of saidcompound.

The labelled compounds of the invention may be useful as diagnostictools, radio tracers, or monitoring agents in various diagnosticmethods, and for in vivo receptor imaging.

The labelled isomer of the invention preferably contains at least oneradio-nuclide as a label. Positron emitting radionuclides are allcandidates for usage. In the context of this invention the radionuclideis preferably selected from ²H (deuterium), ³H (tritium), ¹³C, ¹⁴C,¹³¹I, ¹²⁵I, ¹²³I, and ¹⁸F.

The physical method for detecting the labelled isomer of the presentinvention may be selected from Position Emission Tomography (PET),Single Photon Imaging Computed Tomography (SPECT), Magnetic ResonanceSpectroscopy (MRS), Magnetic Resonance Imaging (MRI), and Computed AxialX-ray Tomography (CAT), or combinations thereof.

Methods of Preparation

The chemical compounds of the invention may be prepared by conventionalmethods for chemical synthesis, e.g. those described in the workingexamples. The starting materials for the processes described in thepresent application are known or may readily be prepared by conventionalmethods from commercially available chemicals.

Also one compound of the invention can be converted to another compoundof the invention using conventional methods.

The end products of the reactions described herein may be isolated byconventional techniques, e.g. by extraction, crystallisation,distillation, chromatography, etc.

Biological Activity

Compounds of the invention may be tested for their ability to inhibitreuptake of the monoamines dopamine, noradrenaline and serotonin insynaptosomes e.g. such as described in WO 97/30997. Based on thebalanced activity observed in these tests the compound of the inventionis considered useful for the treatment, prevention or alleviation of adisease or a disorder or a condition of a mammal, including a human,which disease, disorder or condition is responsive to inhibition ofmonoamine neurotransmitter re-uptake in the central nervous system.

In a special embodiment, the compounds of the invention are considereduseful for the treatment, prevention or alleviation of: mood disorder,depression, atypical depression, depression secondary to pain, majordepressive disorder, dysthymic disorder, bipolar disorder, bipolar Idisorder, bipolar II disorder, cyclothymic disorder, mood disorder dueto a general medical condition, substance-induced mood disorder,pseudodementia, Ganser's syndrome, obsessive compulsive disorder, panicdisorder, panic disorder without agoraphobia, panic disorder withagoraphobia, agoraphobia without history of panic disorder, panicattack, memory deficits, memory loss, attention deficit hyperactivitydisorder, obesity, anxiety, generalized anxiety disorder, eatingdisorder, Parkinson's disease, parkinsonism, dementia, dementia ofageing, senile dementia, Alzheimer's disease, acquired immunodeficiencysyndrome dementia complex, memory dysfunction in ageing, specificphobia, social phobia, social anxiety disorder, post-traumatic stressdisorder, acute stress disorder, drug addiction, drug abuse, cocaineabuse, nicotine abuse, tobacco abuse, alcohol addiction, alcoholism,kleptomania, pain, chronic pain, inflammatory pain, neuropathic pain,migraine pain, tension-type headache, chronic tension-type headache,pain associated with depression, fibromyalgia, arthritis,osteoarthritis, rheumatoid arthritis, back pain, cancer pain, irritablebowel pain, irritable bowel syndrome, post-operative pain,post-mastectomy pain syndrome (PMPS), post-stroke pain, drug-inducedneuropathy, diabetic neuropathy, sympathetically-maintained pain,trigeminal neuralgia, dental pain, myofacial pain, phantom-limb pain,bulimia, premenstrual syndrome, premenstrual dysphoric disorder, lateluteal phase syndrome, post-traumatic syndrome, chronic fatiguesyndrome, urinary incontinence, stress incontinence, urge incontinence,nocturnal incontinence, sexual dysfunction, premature ejaculation,erectile difficulty, erectile dysfunction, premature female orgasm,restless leg syndrome, periodic limb movement disorder, eatingdisorders, anorexia nervosa, sleep disorders, pervasive developmentaldisorders, autism, Asperger's disorder, Rett's disorder, childhooddisintegrative disorder, learning disabilities, motor skills disorders,mutism, trichotillomania, narcolepsy, post-stroke depression,stroke-induced brain damage, stroke-induced neuronal damage, Gilles dela Tourettes disease, tinnitus, tic disorders, body dysmorphicdisorders, oppositional defiant disorder or post-stroke disabilities. Ina preferred embodiment, the compounds are considered useful for thetreatment, prevention or alleviation of depression.

It is at present contemplated that a suitable dosage of the activepharmaceutical ingredient (API) is within the range of from about 0.1 toabout 1000 mg API per day, more preferred of from about 10 to about 500mg API per day, most preferred of from about 30 to about 100 mg API perday, dependent, however, upon the exact mode of administration, the formin which it is administered, the indication considered, the subject andin particular the body weight of the subject involved, and further thepreference and experience of the physician or veterinarian in charge.

Preferred compounds of the invention show a biological activity in thesub-micromolar and micromolar range, i.e. of from below 1 to about 100μM.

Pharmaceutical Compositions

In another aspect the invention provides novel pharmaceuticalcompositions comprising a therapeutically effective amount of thechemical compound of the invention.

While a chemical compound of the invention for use in therapy may beadministered in the form of the raw chemical compound, it is preferredto introduce the active ingredient, optionally in the form of aphysiologically acceptable salt, in a pharmaceutical compositiontogether with one or more adjuvants, excipients, carriers, buffers,diluents, and/or other customary pharmaceutical auxiliaries.

In a preferred embodiment, the invention provides pharmaceuticalcompositions comprising the chemical compound of the invention, or apharmaceutically acceptable salt or derivative thereof, together withone or more pharmaceutically acceptable carriers, and, optionally, othertherapeutic and/or prophylactic ingredients, known and used in the art.The carrier(s) must be “acceptable” in the sense of being compatiblewith the other ingredients of the formulation and not harmful to therecipient thereof.

Pharmaceutical compositions of the invention may be those suitable fororal, rectal, bronchial, nasal, pulmonal, topical (including buccal andsub-lingual), transdermal, vaginal or parenteral (including cutaneous,subcutaneous, intramuscular, intraperitoneal, intravenous,intraarterial, intracerebral, intraocular injection or infusion)administration, or those in a form suitable for administration byinhalation or insufflation, including powders and liquid aerosoladministration, or by sustained release systems. Suitable examples ofsustained release systems include semipermeable matrices of solidhydrophobic polymers containing the compound of the invention, whichmatrices may be in form of shaped articles, e.g. films or microcapsules.

The chemical compound of the invention, together with a conventionaladjuvant, carrier, or diluent, may thus be placed into the form ofpharmaceutical compositions and unit dosages thereof. Such forms includesolids, and in particular tablets, filled capsules, powder and pelletforms, and liquids, in particular aqueous or non-aqueous solutions,suspensions, emulsions, elixirs, and capsules filled with the same, allfor oral use, suppositories for rectal administration, and sterileinjectable solutions for parenteral use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

The chemical compound of the present invention can be administered in awide variety of oral and parenteral dosage forms. It will be obvious tothose skilled in the art that the following dosage forms may comprise,as the active component, either a chemical compound of the invention ora pharmaceutically acceptable salt of a chemical compound of theinvention.

For preparing pharmaceutical compositions from a chemical compound ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glyceride or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized moulds, allowedto cool, and thereby to solidify.

Compositions suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid preparations include solutions, suspensions, and emulsions, forexample, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The chemical compound according to the present invention may thus beformulated for parenteral administration (e.g. by injection, for examplebolus injection or continuous infusion) and may be presented in unitdose form in ampoules, pre-filled syringes, small volume infusion or inmulti-dose containers with an added preservative. The compositions maytake such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulation agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilising and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations, intended for conversionshortly before use to liquid form preparations for oral administration.Such liquid forms include solutions, suspensions, and emulsions. Inaddition to the active component such preparations may comprisecolorants, flavours, stabilisers, buffers, artificial and naturalsweeteners, dispersants, thickeners, solubilizing agents, and the like.

For topical administration to the epidermis the chemical compound of theinvention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilising agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Compositions suitable for topical administration in the mouth includelozenges comprising the active agent in a flavoured base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerine or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Thecompositions may be provided in single or multi-dose form.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract,including intranasal compositions, the compound will generally have asmall particle size for example of the order of 5 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization.

When desired, compositions adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration and continuous infusion are preferred compositions.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences(Maack Publishing Co., Easton, Pa.).

A therapeutically effective dose refers to that amount of activeingredient, which ameliorates the symptoms or condition. Therapeuticefficacy and toxicity, e.g. ED₅₀ and LD₅₀, may be determined by standardpharmacological procedures in cell cultures or experimental animals. Thedose ratio between therapeutic and toxic effects is the therapeuticindex and may be expressed by the ratio LD₅₀/ED₅₀. Pharmaceuticalcompositions exhibiting large therapeutic indexes are preferred.

The dose administered must of course be carefully adjusted to the age,weight and condition of the individual being treated, as well as theroute of administration, dosage form and regimen, and the resultdesired, and the exact dosage should of course be determined by thepractitioner.

The actual dosage depends on the nature and severity of the diseasebeing treated, and is within the discretion of the physician, and may bevaried by titration of the dosage to the particular circumstances ofthis invention to produce the desired therapeutic effect. However, it ispresently contemplated that pharmaceutical compositions containing offrom about 0.1 to about 500 mg of active ingredient per individual dose,preferably of from about 1 to about 100 mg, most preferred of from about1 to about 10 mg, are suitable for therapeutic treatments.

The active ingredient may be administered in one or several doses perday. A satisfactory result can, in certain instances, be obtained at adosage as low as 0.1 μg/kg i.v. and 1 μg/kg p.o. The upper limit of thedosage range is presently considered to be about 10 mg/kg i.v. and 100mg/kg p.o. Preferred ranges are from about 0.1 μg/kg to about 10mg/kg/day i.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.

Methods of Therapy

In another aspect the invention provides a method for the treatment,prevention or alleviation of a disease or a disorder or a condition of aliving animal body, including a human, which disease, disorder orcondition is responsive to inhibition of monoamine neurotransmitterre-uptake in the central nervous system, and which method comprisesadministering to such a living animal body, including a human, in needthereof an effective amount of a chemical compound of the invention.

It is at present contemplated that suitable dosage ranges are 0.1 to1000 milligrams daily, 10-500 milligrams daily, and especially 30-100milligrams daily, dependent as usual upon the exact mode ofadministration, form in which administered, the indication toward whichthe administration is directed, the subject involved and the body weightof the subject involved, and further the preference and experience ofthe physician or veterinarian in charge.

EXAMPLES

The invention is further illustrated with reference to the followingexamples, which are not intended to be in any way limiting to the scopeof the invention as claimed.

General: All reactions involving air sensitive reagents or intermediateswere performed under nitrogen or argon and in anhydrous solvents.

9-Oxo-3-aza-spiro[5.5]undec-7-ene-3-carboxylic acid benzyl ester

Was prepared according to Pandey, A. et al in Bioorg Med. Chem. Lett.11, 2001, 1293-1296.

9-Oxo-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester

To a solution of 9-oxo-3-aza-spiro[5.5]undec-7-ene-3-carboxylic acidbenzyl ester (6.22 g, 20.8 mmol), di-tert-butyl dicarbonate (6.81 g,31.2 mmol) and potassium carbonate (5.75 g, 41.6 mmol) in ethanol/water(9:1, 200 mL), palladium on carbon (221 mg, 2.08 mmol) was added and themixture stirred under a hydrogen atmosphere overnight. The mixture wasfiltered over celite and the celite pad was washed with ethanol andethyl acetate. The filtrate was evaporated to dryness and re-dissolvedin ethyl acetate and water. The aqueous phase was extracted twice withethyl acetate. The combined organic phase was washed with brine, dried(sodium sulfate), filtered and evaporated to give a colourless oil.Flash chromatography (heptane/ethyl acetate 3:1 to 1:1) gave 2.83 g(51%) of 9-oxo-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butylester.

9-Hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester

9-Oxo-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (1 g,3.74 mmol) and cerium(III) chloride heptahydrate (1.39 g, 3.74 mmol) inmethanol (40 mL) was cooled to −78° C. and sodium borohydride (141 mg,3.74 mmol) was added in 4 portions. The mixture was warmed up to −20° C.and stirred for 30 min. Water was added and the mixture was concentratedin vacuo. The aqueous layer was extracted three times with ethylacetate. The combined organic phase was washed with brine, dried (sodiumsulfate), filtered and evaporated to give 883 mg (88%) of9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester asa colourless oil.

Method A

9-(3,4-Dichloro-phenoxy)-3-aza-spiro[5.5]undecane trifluoroacetic acidsalt

Diisopropylazo dicarboxylate (315 mg, 1.56 mmol) in diethyl ether (2 mL)was added slowly to an ice cooled solution of triphenylphosphine (582mg, 2.22 mmol) in diethyl ether (5 mL). The reaction mixture was stirredfor 20 min. 3,4-Dichlorophenol (290 mg, 1.78 mmol) in diethyl ether (2mL) was added and stirred 30 min at 0° C. and9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester(400 mg, 1.48 mmol) in diethylether (5 mL) was added and the mixturestirred at room temperature over night. Evaporation followed by flashchromatography (heptane/ethylacetate 9:1) gave 340 mg (56%) of9-(3,4-dichloro-phenoxy)-3-aza-spiro[5.5]undecane-3-carboxylic acidtert-butyl ester.

9-(3,4-Dichloro-phenoxy)-3-aza-spiro[5.5]undecane-3-carboxylic acidtert-butyl ester (340 mg, 0.82 mmol) was dissolved in dichloromethane (8mL) and cooled on an ice bath. Trifluoroacetic acid (2 mL) was added andstirred for 2 h at room temperature. Evaporation followed byco-evaporation with toluene and ethyl acetate gave a solid compound. Thecompound was washed with diethyl ether to give 222 mg (63%) of9-(3,4-dichloro-phenoxy)-3-aza-spiro[5.5]undecane trifluoroacetic acidsalt as a white crystalline compound. Mp. 139, 6-141.2° C.

9-(6-Methoxy-Naphthalen-2-yloxy)-3-aza-spiro[5.5]undecane

Was prepared according to method A from 6-methoxy-2-naphthol and9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester.

Mp. 111.8-113.5° C.

7-(3-Aza-spiro[5.5]undec-9-yloxy)-chromen-2-one

Was prepared according to method A from 7-hydroxycoumarin and9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester.

Mp. 126-128° C.

9-(3-Bromo-4-chloro-phenoxy)-3-aza-spiro[5.5]undecane

Is prepared according to method A.

9-(4-Chloro-phenoxy)-3-aza-spiro[5.5]undecane

Was prepared according to method A from 4-chlorophenol and9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester.Mp. 140-142° C.

9-(4-Chloro-3-fluoro-phenoxy)-3-aza-spiro[5.5]undecane

Is prepared according to method A.

9-(3-Chloro-4-fluoro-phenoxy)-3-aza-spiro[5.5]undecane

Is prepared according to method A.

9-(4-Chloro-3-trifluoromethyl-phenoxy)-3-aza-spiro[5.5]undecane

Is prepared according to method A.

9-(Naphthalen-2-yloxy)-3-aza-spiro[5.5]undecane

Was prepared according to method A from 2-naphthol and9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester.Mp. 132.2-133.8° C.

6-(3-Aza-spiro[5.5]undec-9-yloxy)-chromen-2-one

Was prepared according to method A from 6-hydroxycoumarin and9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester.Mp. 192.9-193.6° C.

(3-Aza-spiro[5.5]undec-9-yl)-(3,4-dichloro-phenyl)-amine

3,4-Dichloroaniline (364 mg, 2.2 mmol), sodium triacetoxyborohydride(889 mg, 4.20 mmol) and acetic acid (0.24 mL, 4.20 mmol) were added to asolution of 9-oxo-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butylester (561 mg, 2.10 mmol) in 1,2-dichloroethane (30 mL) with crunched 4Amol sieves (10 g). The mixture was stirred a room temperature overnight. Additional 4A mol sieves (12 g) and sodium triacetoxyborohydride(445 mg) was added and the mixture was stirred over night. The reactionwas quenched with water and 5% citric acid was added. The mixture wasfiltered through kieselguhr and the filtrated was evaporated until onlythe aqueous layer remained. The aqueous layer was extracted with ethylacetate (3×50 mL) and the combined organic phases were washed withbrine, dried with sodium sulphate, filtered and evaporated to give thecrude product. Flash chromatography (ethyl acetale/heptane) gave9-(3,4-dichloro-phenylamino)-3-aza-spiro[5.5]undecane-3-carboxylic acidtert-butyl ester (258 mg, 0.624 mmol, 30%).

To an ice-cooled solution of9-(3,4-dichloro-phenylamino)-3-aza-spiro[5.5]undecane-3-carboxylic acidtert-butyl ester (258 mg, 0.624 mmol) in dichloromethane (10 mL) asolution of trifluoroacetic acid (4 mL) in dichloromethane (5 mL) wasadded. The mixture was stirred a room temperature over night. Water wasadded followed by sodium hydroxide 3 M to pH 9-10. The aqueous layer wasextracted with dichloromethane (4×40 mL). The combined organic layerswere washed with brine, dried with sodium sulphate and evaporated togive (3-aza-spiro[5.5]undec-9-yl)-(3,4-dichloro-phenyl)-amine (164 mg84%) as a brownish solid. Mp. 128-132° C.

9-(3,4-Dichloro-phenoxy)-3-methyl-3-aza-spiro[5.5]undecane

To a ice cooled solution of9-(3,4-dichloro-phenoxy)-3-aza-spiro[5.5]undecane-3-carboxylic acidtert-butyl ester (60 mg, 0.19 mmol) in dichloroethane (10 mL),formaldehyde (37% in water, 54 μL, 0.72 mmol) was added and stirred for1 h at 0° C. Sodium triacetoxyborohydride (102 mg, 0.48 mmol) was addedand stirred over night at room temperature. The reaction was quenchedwith aqueous sodium hydrogen-carbonate and evaporated. The remainingaqueous phase was extracted four times with dichloromethane and thecombined organic phase was dried (sodium sulfate), filtered andevaporated to give 75 mg (95%)9-(3,4-dichloro-phenoxy)-3-methyl-3-aza-spiro[5.5]undecane as a yellowoil. LC-ESI-HRMS of [M+H]+ shows 328.1249 Da. Calc. 328.123495 Da, dev.4.3 ppm.

Test Example In Vitro Inhibition Activity

A number of compounds were tested for their ability to inhibit thereuptake of the monoamine neurotransmitters dopamine (DA) noradrenaline(NA) and serotonine (5-HT) in synaptosomes as described in WO 97/16451.

The test values are given as IC₅₀ (the concentration (μM) of the testsubstance which inhibits the specific binding of ³H-DA, ³H-NA, or³H-5-HT by 50%).

Test results obtained by testing selected compounds of the presentinvention appear from the below table:

TABLE 1 DA- NA- 5-HT- uptake uptake uptake Test compound IC₅₀(μM)IC₅₀(μM) IC₅₀(μM) 3^(rd) compound of method A; 1.2 0.086 0.00207-(3-Aza-spiro[5.5]undec-9- yloxy)-chromen-2-one 2^(nd) last compound of0.49 1.0 0.0023 method A; (3-Aza-spiro[5.5]undec-9-yl)-(3,4-dichloro-phenyl)-amine

1-13. (canceled)
 14. A compound of Formula I:

any of its stereoisomers or any mixture of its stereoisomers, or apharmaceutically acceptable salt thereof; wherein R^(a) representshydrogen or alkyl; which alkyl is optionally substituted with one ormore substituents independently selected from the group consisting of:halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, nitro,alkoxy, cycloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl andalkynyl; and R^(b) represents an aryl or a heteroaryl group; which arylor heteroaryl group is optionally substituted with one or moresubstituents independently selected from the group consisting of: halo,trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, alkoxy,cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, methylenedioxy,ethylenedioxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl,—NR′R″, —(C═O)NR′R″ or —NR′(C═O)R″; wherein R′ and R″ independent ofeach other are hydrogen or alkyl X represents —O— or —NR^(c)—; whereinR^(c) represents hydrogen or alkyl.
 15. The compound of claim 14, or apharmaceutically acceptable salt thereof, wherein R^(a) representshydrogen or alkyl.
 16. The compound of claim 14, or a pharmaceuticallyacceptable salt thereof, wherein R^(b) represents a phenyl group, whichphenyl group is optionally substituted with one or more substituentsindependently selected from the group consisting of: halo,trifluoromethyl, trifluoromethoxy, cyano and alkoxy.
 17. The compound ofclaim 14, or a pharmaceutically acceptable salt thereof, wherein R^(b)represents a phenyl group, which phenyl group is substituted once ortwice with substituents independently selected from the group consistingof: halo, trifluoromethyl, trifluoromethoxy, cyano and alkoxy.
 18. Thecompound of claim 14, or a pharmaceutically acceptable salt thereof,wherein R^(b) represents a naphthyl group, which naphthyl group isoptionally substituted with one or more substituents independentlyselected from the group consisting of: halo, trifluoromethyl,trifluoromethoxy, cyano and alkoxy.
 19. The compound of claim 14, or apharmaceutically acceptable salt thereof, wherein R^(b) represents anoptionally substituted coumarinyl group.
 20. The compound of claim 14,or a pharmaceutically acceptable salt thereof, wherein X represents —O—or —NH—.
 21. The compound of claim 14, which is9-(3,4-Dichloro-phenoxy)-3-aza-spiro[5.5]undecane;9-(6-Methoxy-naphthalen-2-yloxy)-3-aza-spiro[5.5]undecane;7-(3-Aza-spiro[5.5]undec-9-yloxy)-chromen-2-one;9-(3-Bromo-4-chloro-phenoxy)-3-aza-spiro[5.5]undecane;9-(4-Chloro-phenoxy)-3-aza-spiro[5.5]undecane;9-(4-Chloro-3-fluoro-phenoxy)-3-aza-spiro[5.5]undecane;9-(3-Chloro-4-fluoro-phenoxy)-3-aza-spiro[5.5]undecane;9-(4-Chloro-3-trifluoromethyl-phenoxy)-3-aza-spiro[5.5]undecane;9-(Naphthalen-2-yloxy)-3-aza-spiro[5.5]undecane;6-(3-Aza-spiro[5.5]undec-9-yloxy)-chromen-2-one;(3-Aza-spiro[5.5]undec-9-yl)-(3,4-dichloro-phenyl)-amine;9-(3,4-Dichloro-phenoxy)-3-methyl-3-aza-spiro[5.5]undecane; or apharmaceutically acceptable salt thereof.
 22. A pharmaceuticalcomposition, comprising a therapeutically effective amount of a compoundof claim 14, any of its stereoisomers or any mixture of itsstereoisomers, or a pharmaceutically acceptable salt thereof, togetherwith at least one pharmaceutically acceptable carrier, excipient ordiluent.
 23. A method for treatment, prevention or alleviation of adisease or a disorder or a condition of a living animal body, includinga human, which disorder, disease or condition is responsive toinhibition of monoamine neurotransmitter re-uptake in the centralnervous system, which method comprises the step of administering to sucha living animal body in need thereof a therapeutically effective amountof a compound according to claim 14, any of its stereoisomers or anymixture of its stereoisomers, or a pharmaceutically acceptable saltthereof.
 24. The method according to claim 23, wherein the disease,disorder or condition is mood disorder, depression, atypical depression,depression secondary to pain, major depressive disorder, dysthymicdisorder, bipolar disorder, bipolar I disorder, bipolar II disorder,cyclothymic disorder, mood disorder due to a general medical condition,substance-induced mood disorder, pseudodementia, Ganser's syndrome,obsessive compulsive disorder, panic disorder, panic disorder withoutagoraphobia, panic disorder with agoraphobia, agoraphobia withouthistory of panic disorder, panic attack, memory deficits, memory loss,attention deficit hyperactivity disorder, obesity, anxiety, generalizedanxiety disorder, eating disorder, Parkinson's disease, parkinsonism,dementia, dementia of ageing, senile dementia, Alzheimer's disease,acquired immunodeficiency syndrome dementia complex, memory dysfunctionin ageing, specific phobia, social phobia, social anxiety disorder,post-traumatic stress disorder, acute stress disorder, drug addiction,drug abuse, cocaine abuse, nicotine abuse, tobacco abuse, alcoholaddiction, alcoholism, kleptomania, pain, chronic pain, inflammatorypain, neuropathic pain, migraine pain, tension-type headache, chronictension-type headache, pain associated with depression, fibromyalgia,arthritis, osteoarthritis, rheumatoid arthritis, back pain, cancer pain,irritable bowel pain, irritable bowel syndrome, post-operative pain,post-mastectomy pain syndrome (PMPS), post-stroke pain, drug-inducedneuropathy, diabetic neuropathy, sympathetically-maintained pain,trigeminal neuralgia, dental pain, myofacial pain, phantom-limb pain,bulimia, premenstrual syndrome, premenstrual dysphoric disorder, lateluteal phase syndrome, post-traumatic syndrome, chronic fatiguesyndrome, urinary incontinence, stress incontinence, urge incontinence,nocturnal incontinence, sexual dysfunction, premature ejaculation,erectile difficulty, erectile dysfunction, premature female orgasm,restless leg syndrome, periodic limb movement disorder, eatingdisorders, anorexia nervosa, sleep disorders, pervasive developmentaldisorders, autism, Asperger's disorder, Rett's disorder, childhooddisintegrative disorder, learning disabilities, motor skills disorders,mutism, trichotillomania, narcolepsy, post-stroke depression,stroke-induced brain damage, stroke-induced neuronal damage, Gilles dela Tourettes disease, tinnitus, tic disorders, body dysmorphicdisorders, oppositional defiant disorder or post-stroke disabilities.